Results from UKALL60+, a phase 2 study in older patients with untreated acute lymphoblastic leukemia

Poor outcome for older patients with ALL has multiple attributions, including a higher incidence of high ‐ risk genetic features, 1 and comorbidities as well as treatment intolerance. 2,3 The phase 2 clinical trial UKALL60+ (NCT01616238) was a collaboration between the UK National Cancer Research Institute Adult ALL Group and the Haemato ‐ Oncology Foundation for Adults in the Netherlands (HOVON) to study treatment choices, quality of life (QoL) and outcomes in older patients with ALL. UKALL60+ offered four treat-ment “ pathways ” : pathway A for BCR::ABL1 + ALL and pathways B, C, and D offering three choices of intensity for BCR::ABL1 negative ALL (Intensive, Intensive ‐ plus and Non ‐ Intensive, respectively), to be selected by investigator and patients. A registration ‐ only choice (Pathway E) was also available. Details of treatment regimens are given in Figure S1. There were no exclusions for any comorbidities. The primary endpoint was complete remission (CR) after a 2 ‐ phase induction. Secondary endpoints included event ‐ free survival (EFS) and overall survival (OS), the predictive value of MRD (Ig/TCR quantification, EuroMRD criteria), 4

Significant differences were seen in duration of inpatient stay, analysed by percentage of total treatment period spent in hospital (p = 0.026).Patients receiving pathways B and C spent more treatment-time in hospital compared to pathways A and D, with the effect most pronounced during induction (p = 0.0001) where pathway B and C participants were inpatients for 62.1% (46.3-96.7)and 75.8% (68.8-83.0),respectively compared to pathway A and D participants at 22.8% (IQR: 9.8-55.6)and 31.1% (IQR: 14.5-51.5),respectively.QoL was compared by pathway-summarized in supplementary results.We saw no indication that the least intensive pathway D provided a better QoL, with scores for some scales numerically lower than those of pathways A-C (Figure S4A-D).Any decreases in QoL from baseline were generally seen at the end of induction phases, with improvements in the FACT scores seen by the end of consolidation 1 and maintenance 1 (Table S8).Physical function scores, as assessed by QLQ-C30, remained reduced throughout while sensory and motor neuropathy scores increased at later points during therapy.
Our survival data are broadly commensurate with data from a GMALL cohort of similar median age 6 where OS at 3 years was 32%.However, the UKALL60+ population were in worse health overall; 27.5% had a Charlson Index >7 compared to the GMALL cohort, with only 11% scoring >3, commensurate with the GMALL exclusion criteria for comorbidities.By contrast to the GMALL early death rate of 14%, we observed a low treatment-related mortality.UKALL60+ treatments were successfully planned to minimize harm, but this did not improve OS.
It was unexpected that the 3-year EFS and OS of 20.5% and 25.2% for those aged 60-65 years treated on UKALL14 data did not differ from that of the UKALL60+ recruits, with completely overlapping survival curves (Figure 1).The outcomes are similar to those reported in an EBMT study of 418 patients aged over 55 years receiving alloSCT; 5-year LFS of 34% but a 51% nonrelapse mortality. 7Taken together, these data suggest even the most intensive treatments including alloSCT do not generate excellent outcomes for most older patients with ALL.We were surprised to see no evidence of better QoL for the recipients of the least intensive pathway D, despite a significant reduction in length of hospital stay.
In summary, the UKALL60+ pathways proved safe for initial cytoreduction, but the survival outcomes in this representative population of older patients with ALL was unsatisfactory.Nonchemotherapy approaches should be employed at the earliest opportunity for this patient group.QoL should always be measured, as the investigators assumptions do not necessarily reflect patients' experience.

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I G U R E 1 Kaplan-Meier survival curves.(A, B) Kaplan-Meier survival curves by UKALL60+ treatment pathways with (A) event-free survival (EFS) and (B) overall survival (OS).(C, D) Kaplan-Meier survival curves for overall outcomes among UKALL60+ cohort and the UKALL14 60-to 65-year-old participants with (C) EFS and (D) OS.Note that one pathway E UKALL60+ registrant received the UKALL14 protocol and is included in the UKALL14 cohort only.